1. Field of the Invention
The present invention relates to hydrogels and, more particularly, to methods of making hydrogels utilizing controlled hydrolysis by self-termination.
2. Information Disclosure Statement
Polyacrylonitrile (PAN) polymers are frequently used for fabrication of membranes, for manufacture of textile fibers, for production of carbon fibers and hydrogels, or as engineering plastics. Their composition vary widely from pure PAN homopolymer to copolymers of acrylonitrile (AN) with to about 20% molar of various comonomers. AN is typically combined either with hydrophilic co-monomers (such as acrylamide, vinyl pyrrolidone, styrene sulfonic acid, vinylsulfonic acid etc.) or with hydrophobic comonomers (such as alkyl acrylates or methacrylates, styrene, vinylchloride, methylstyrene, vinylpyrridine etc.). Such copolymers are usually considered to be PAN as long as they still retain the main characteristics of PAN, namely, high crystallinity and high melting point in absence of PAN solvents. PAN is practically unmeltable because its melting temperature (theoretically over 320.degree. C.) is higher than its decomposition temperature (PAN becomes discolored at temperatures above about 150.degree. C. and above about 200.degree. C. it turns into insoluble, non-meltable precursors of graphite).
PAN has a unique crystalline structure with main X-ray diffraction periodicity of about 5.2 Angstroms, insensitivity to stereo-regularity of the polymer and lateral organization of crystallites in oriented states. Other typical properties of PAN are excellent environmental stability and high tensile strength, particularly in oriented state.
As other non-meltable polymers (e.g., aramides), PAN have to be processed from solutions in suitable solvents (such as DMSO, DMF, concentrated solutions of ZnCl.sub.2 and some other) using a suitable "wet" method (for instance, by coagulation, dry spinning etc.)
Some of the AN copolymers are rendered meltable by introduction of suitable comonomers. Such copolymers are processable by usual plastic-processing methods such as extrusion or injection molding. However, this cannot be achieved without a substantial destruction of crystalline structure and loss of certain valuable properties, such as high thermal stability. There is a substantial structural difference between meltable "modacrylic" copolymers and non-meltable PAN.
AN is sometimes combined with highly polar comonomers to increase its hydrophilicity and improve certain desirable properties such as dyeability of textile fibers, wettability of separation membranes, and the like. PAN copolymers with hydrophilic comonomers are sometimes used to form hydrogels, i.e. water-insoluble elastomers containing large amount of water. Hydrogels are particularly useful for biomedical products such as implants, wound dressings, contact lenses, bioseparation membranes and lubricious coatings.
Hydrogels can be either of a conventional "thermoset" type with a covalent network, or "thermoplastic" hydrogels with physical network formed by interactions between hydrophobic groups. Covalently crosslinked PAN-based hydrogels are sometimes synthesized by a combination of polymerization of AN monomer in aqueous solvents, such as concentrated solutions of ZnCl2 or HNO3. Hydrophilic comonomers are often derivatives of acrylic acid, such as salts, esters, amides, amidines, hydrazidines and the like. If such comonomers are copolymerized with AN, they are randomly distributed in the PAN chain. Copolymerization of AN with hydrophilic comonomers in concentrated zinc chloride solutions to form crosslinked hydrogels is described in U.S. Pat. No. 3,812,071 (A. Stoy). Modification of PAN properties by copolymerization with carboxylated co-monomers and subsequent treatment with alkalies is described in U.S. Pat. No. 4,272,422 (Tanaka). A relatively low concentration of randomly distributed hydrophilic monomers is needed to achieve solubility in water or very high swelling. This is because the crystallization capability requires a certain minimum length of the sequence of nitrile groups in 1,3 positions. As the length of continuous sequences of AN units (ie., the sequence of AN units between two non-AN units) decreases with increasing content of randomly distributed non-AN comonomers, so decrease crystallinity, thermal stability and other useful properties of PAN polymers. It was observed that properties of such hydrogels can be improved if polymerization or copolymerization of AN and aqueous inorganic solvents is followed by acid-catalyzed hydrolysis, as it is described in U.S. Pat. No. 4,123,406 (A. Stoy et al.), U.S. Pat. No. 4,172,823 (A. Stoy et al.) and U.S. Pat. No. 4,228,056 (A. Stoy).
It was postulated that improved properties in hydrolyzed PAN is due to a complementary physical network. In many cases, the physical network formed by a controlled partial hydrolysis of PAN is stable enough and additional covalent network is unnecessary.
Such a hydrolysis is typically carried out by using acid catalysis leading to formation of multi-block copolymers (MBC) with alternating sequences of acrylonitrile and acrylamide units. PAN solvents useful for acid hydrolysis are typically concentrated aqueous ZnCl.sub.2 solutions, as described in U.S. Pat. No. 2,837,492 (Stanton et al.) and U.S. Pat. No. 3,987,497 (A. Stoy et al) or in concentrated inorganic acids, such as sulfuric acid, nitric acid, phosphoric acid and mixtures thereof. Such process is described, for example, in the U.S. Pat. No. 3,926,930 (Ohfuka et al.), U.S. Pat. No. 3,709,842 (A. Stoy), U.S. Pat. No. 4,026,296 (A. Stoy et al.), U.S. Pat. No. 4,173,606 (V. Stoy et al.) and U.S. Pat. No. 4,183,884 (Wichterle et al.).
The physical network in PAN-based hydrogels can be formed by clusters of polyacrylonitrile sequences. Physically crosslinked PAN hydrogels have their nitrile groups (AN units) and hydrophilic groups organized in alternating sequences, forming so-called "Multi-Block Copolymers" (MBC). If AN sequences (also called "Hard blocks") are sufficiently long, they separate in presence of water from sequences of hydrophilic units (also called "Soft Blocks") to form the network-forming crystalline clusters. A certain minimum length of the Hard block is necessary for the phase separation. Moreover, certain length of Hard Block is required to build a stable crystalline cluster. Actual minimum lengths of Hard Blocks are not known. According to some estimates, only hard blocks with 5 or more nitrile units are effective in building the network-forming clusters.
One can appreciate that the phase separation in the MBC is not clean or perfect. Each crystalline cluster will contain some hydrophilic groups that are disturbing its organization. Crystalline clusters will have also a broad distribution of sizes. Consequently, crystalline clusters will have a broad distribution of melting points and resistance of the cluster to the local stress. Such hydrogels typically show limited thermal stability and distinct creep behavior under stress. The longer the hard blocks and more uniform their length in a MBC, the better thermal and mechanical stability in the resulting hydrogel.
AN-containing MBCs are produced by suitable reactions of PAN (typically hydrolysis or aminolysis) converting pendant nitrile groups into hydrophilic derivatives of acrylic acid. The reactions leading to MBC are so called "Zipper reactions" in which nitrile groups adjacent to already reacted group (i.e., an acrylic acid derivative other than nitrile) are more reactive than nitrile groups adjacent to other nitriles (which is the basic arrangement in the original PAN homopolymer). Hydrophilic "Soft Blocks" are initiated by a relatively slow reaction of a nitrile flanked by other nitriles on both sides. Once a new pendant group is introduced, the "Soft Blocks" can grow by a faster propagation reaction. The propagation of the Soft Block continues until reaction consumes all available nitrile groups in the given polymer chain, unless the reaction is terminated before the nitrile consumption is completed. If all nitriles are consumed, the product is a water-soluble acrylic polymer (useful, for instance, as an additive to drilling mud in oil production).
To form a MBC, more than one "Soft Block" has initiated in each chain. Formation of MBC requires specific relations between molecular weight and rates of initiation, propagation and termination rates of the Zipper reaction. If these conditions are not met, the reaction yields a random copolymer, an alternating copolymer, blend of homopolymers or other intermediate unsuitable for hydrogel fabrication. Even if MBC is formed, its average length of blocks and lengths of block distribution may vary in a broad range depending on the reaction kinetics. General analysis of zipper reaction products is provided, for instance, by N. Plate et al., in Journal of Polymer Science: Polymer Chemistry Edition, Vol. 12, 2165-2185 (1974). In practical terms, the sequential analysis requires knowledge of rate constants of elementary reactions. Such methods are described, e.g., by V. Stoy in Journal of Polymer Science: Polymer Chemistry Edition, Vol. 13, 1175-1182 (1975) and Journal of Polymer Science: Polymer Chemistry Edition, Vol. 15, 1029-1033 (1977).
From the aforementioned follows that controllable and reproducible fabrication of stable thermoplastic hydrogels requires unusual level of control over the reaction kinetics (reaction rates of most reactions typically effects only the process economy. In the case of MBCs reaction kinetics also directly affects the product quality.) The reaction control is required on several levels:
To synthesize a useful MBC, the zipper reaction has to be stopped at a preset partial conversion. This is a rather unusual requirement for a chemical reaction where a maximum conversion is usually desirable. The reaction conversion can be, in principle, limited by availability of one of the co-reagent. Such reaction would be "self-terminating" at the conversion when one of the reacting components is depleted. Because we require a specific but limited conversion of nitrile groups, its coreagent has to be present in a lesser molar concentration than nitrile groups. This is particularly difficult in case of hydrolysis because water is present in a large molar excess as part of the reaction.
The self-termination is sometimes possible in the case of heterogeneous, alkali-catalyzed hydrolysis of PAN (a.k.a. saponification) at elevated temperatures that is used to produce water-soluble or super-absorbent acrylic polymers. U.S. Pat. No. 2,812,317 (Barret et al.) describes a direct multi-step saponification of aqueous PAN emulsions by alkali metal hydroxides at an elevated temperature. According to Barret, saponification under these conditions is a stochiometric reaction of nitrile with hydroxide yielding carboxylate. Therefore, one molecule of hydroxyde is consumed for each reacted nitrile group and the alkali metal hydroxide can be added in each step in a limited amount to be consumed by the saponification process.
Similar process used to produce water-soluble polymers of acrylic acid by saponification of PAN slurries is described in U.S. Pat. No. 2,861,059 (Mowry et al.). The saponification is carried out in presence of water-miscible liquids that are poor solvents for both PAN and saponification products. Because the goal is a substantially complete saponification, the amount of hydroxide is not critical as long as the final product is water-soluble.
Partial saponification of acrylic fibers in presence of a high concentration of alkali metal hydroxide is described in the U.S. Pat. No. 4,366,206 (Tanaka). High concentration of the hydroxyde or other electrolytes causes a change of mechanism so that the product of saponification is a crosslinked hydrogel rather than water-soluble acrylate polymer. Composition of the reagent liquid can be changed by addition of various organic or inorganic substances as long as it does not dissolve PAN fibers. The described saponification process is carried out in the molar excess of hydroxide. Therefore, reaction conversion (i.e., the thickness of the outer hydrogel jacket) has to be controlled by the reaction time.
Improvement of the above process is described in U.S. Pat. No. 4,374,175 (Tanaka). The improvement consists in contacting PAN fibers with only a limited amount of the reagent so that the reaction can proceed only to a certain depth, leaving the fiber core intact. The process has to be run at a high temperature to achieve a high reaction rate and to allow the control of the thickness of the hydrogel layer. U.S. Pat. No. 5,496,890 (Sackmann et al.) describes superabsorbent polymers prepared by direct partial saponification of PAN dispersions. The product contains 30 to 60 mol. % of carboxylate groups, 20 to 60% of carbonamide groups, 10 to 20% of residual nitrile groups and its swelling capacity is up to 1000 grams of water on 1 gram of polymer. The process uses contacting a dispersed PAN particles with aqueous solution of an alkali metal hydroxide, in amount corresponding to more than one mol of hydroxide per one mol of converted nitrile. Reaction conversion is monitored by amount of released ammonia and terminated by neutralization of excess of hydroxide reagent by addition of an acid, e.g. a hydrochloric acid.
The last five references show that saponification of solid PAN has different mechanism than solution reactions of PAN and yield products of different compositions that are not MBCs. Solution reactions of PAN are typically carried out with a large excess of the co-reagent. For that reason, it was not possible to use self-termination control in any of the hitherto known processes for MBC production. In all cases described so far, PAN hydrolysis is terminated by coagulation of the intermediate MBC and/or extraction or neutralization of the reaction components such as solvents and catalysts, at some time when the desired conversion was presumably achieved. Control of the end-point by time is very difficult because it requires a precise control of the reaction rate which is sensitive to variation in temperature, concentrations and other variables. Moreover, it is difficult to terminate the reaction at the same time for all polymer chains, particularly if the reaction is carried out on an industrial scale. This contributes to heterogeneity of the product, since not all polymer chains have the same composition. (i.e., conversion distribution).
As indicated in the above description, there are numerous technical problems with PAN hydrolysis processes that use the same compound as a solvent and a catalyst. These problems lead to heterogeneity and poor crystallinity of these products, as manifested by their meltability in presence swelling agents that are not solvents of PAN, such as water and glycerol. This is an advantage for processing these hydrogels from simple melts, as described in the U.S. Pat. No. 4,053,442 (Jungr et al.) Several patents proposed control of heterogeneity and sequential composition of products by various means (U.S. Pat. No. 3,897,382 (V. Stoy et al.) and U.S. Pat. No. 3,948,870 (V. Stoy et al.), but could not solve the fundamental problem of the reaction endpoint.
The previously described solution hydrolysis of PAN uses an acid catalysts. Base-catalyzed PAN hydrolysis can be also carried out in solutions. In this case, the mechanism is different from acid-catalyzed hydrolysis as well as from the above described base-catalyzed heterogeneous hydrolysis. Not only is the mechanism different, but the reaction product has a different chemical composition and structure. Such a process is described in U.S. Pat. No. 4,107,121 (V. Stoy) involving a homogenous base-catalyzed hydrolysis of PAN dissolved in aqueous rhodanide solution. The described reaction can be catalyzed by various bases, including ammonia, tertiary amines, carbonates and hydroxides of alkali metals. This reaction yields anionic polymers with just a minor concentration of other reaction products, such as acrylamide. The resulting polymers are thermally unstable since can be melted even in dry state. This indicates low, if any, crystallinity of PAN clusters. Once swelled in water, resulting hydrolyzates can be molten at temperatures as low as 75.degree. C., unless they are covalently crosslinked. The hydrolyzates prepared by this method are often spontaneously covalently crosslinked by side reactions of nitrile groups.
The reaction described in U.S. Pat. No. 4,107,121 is not self-terminating since water from the solvent is present in a large molar excess. Besides, the described reaction is catalyzed even by ammonia that is one of the reaction products. The manufacturing method requires reaction termination by removing the catalyst either by neutralization or by washing.
Because of the termination control problems with solution hydrolysis of PAN, hydrolytic and other reactions of PAN are sometimes carried out in so called so called "aquagel state" that combines certain properties of heterogeneous and solution reaction systems. This process is described in the U.S. Pat. No. 4,943,618 (V. Stoy et al.). According to this patent, PAN is first brought into the aquagel state that is permeable for water-miscible reagents. CN groups in aquagel state are reactive similarly as in the solution. Consequently, aquagel can participate in many reactions, including acid or base catalyzed hydrolysis, aminolysis, alcoholysis, hydrazinolysis, Ritter and other reactions. This system allows monitoring of reaction conversion by measuring swelling of the product in the reaction mixture. This simplifies somewhat the end-point detection. Although such described hydrolytic reactions are not self-terminating and have to be quenched by removal of the catalyst, simplified end-point detection allows better control over the final product conversion and thus better reproducibility.
However, heterogeneous reactions are always diffusion-controlled at least to some extent, leading to higher conversion on the solid-liquid interface than in the bulk of the solid particle. This further contributes to the product heterogeneity via a broad distribution of conversion among polymer chains. In many cases, MBC copolymers coexist with still unreacted PAN. This is sometimes deemed an advantage for hydrophilic fibers or sluries such as described in the previously discussed Tanaka's patents, or membranes and low-swelling hydrogels for catheters and other devices, as described in the U.S. Pat. Nos. 4,379,874 and 4,420,589 (both V. Stoy). The last two patents suggest using homopolymer PAN as an additive to stabilize the crystalline clusters in the hydrogel. This is designed to bypass inherent problems with controlling MBC sequential composition via reaction kinetics. However, this measure is more suitable for hydrophilic polymers and hydrogels with low water content than for highly swelling hydrogels. Heterogeneous products are not suitable for medical-grade hydrogels with a high water content and for many applications, such as ophthalmic lenses. In other cases, MBC coexist with fully hydrolyzed, water-soluble polymers that can diffuse uncontrollably from such hydrogels over long time periods. In some case all three types of polymers (i.e., unreacted PAN; MBC; and water-soluble acrylate) can coexist in one product. Such complexity complicates control over the properties and is hardly suitable for biomedical polymers.
From other prior art describing PAN modifications other than hydrolysis, it is worth mentioning U.S. Pat. No. 5,252,692 (Lovy et al.). This patent describes aminolysis of PAN by reaction between nitriles and primary amines, yielding copolymers comprising N-substituted amides and N-substituted amidines as the main reaction product. This reaction can be carried out both as a solution reaction and as a heterogeneous reaction. Although the self-termination is not mentioned specifically, the maximum conversion of aminolysis can be, at least in theory, controlled by molar ration CN/primary amine in the reaction mixture. In practical terms, however, this reaction cannot be considered self-terminating because the competing hydrolytic reaction cannot be controlled in the same way.
From the above description of Prior Art is obvious that hydrolysis of PAN is a very complicated reaction which outcome is very dependent on reaction conditions, including nature of catalyst, temperature, concentrations, presence and type of PAN solvent and other parameters. It is also obvious that hitherto known reaction mixtures yielding acrylic MBCs are inherently unstable so that reaction has to be terminated and product isolated at a precisely defined moment. These factors complicate production and decrease utility of acrylic MBCS.
Notwithstanding the prior art, the present invention is neither taught nor rendered obvious thereby.